State-dependent peripheral neuromodulation to treat bladder dysfunction

ABSTRACT

The present invention relates to a neuromodulation apparatus and methods of using the neuromodulation apparatus for treating bladder dysfunction.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/897,392, filed Jun. 10, 2020, which is a continuation of U.S.application Ser. No. 15/767,400, filed Apr. 11, 2018, now U.S. Pat. No.10,722,708, which is a national stage filing under 35 U.S.C. 371 ofinternational patent application number PCT/US2016/057043, filed Oct.14, 2016, which claims the benefit under 35 U.S.C. § 119(e) of U.S.provisional application number 62/241,825, filed Oct. 15, 2015, theentire contents of each of which are incorporated herein by reference intheir entireties.

BACKGROUND

Efficient bladder function, mediated by continence and micturitionreflexes, is accomplished through coordinated sympathetic,parasympathetic and somatic neural activity [Beckel and HolstegeNeurophysiology of the Lower Urinary Tract, in Urinary Tract (2011)Springer Berlin Heidelberg, 149-169].

Treatments for bladder dysfunction include behavioural therapy, exercisetherapy, and pharmacotherapy. Behavioural and exercise therapy havelimited efficacy, and pharmacotherapy has dose-limiting side effects.Overactive bladder (OAB), resulting in urgency, frequency andincontinence, is a highly prevalent condition that leads to medicalcomplications and decreased quality of life [Latini & Giannantoni(2011), Expert Opinion on Pharmacotherapy 12:1017-1027].

In patients who are non-responsive or whose condition is inadequatelycontrolled by conservative treatments, attempts have been made tocontrol the functioning of the urinary bladder using electrical devices,as summarized by Gaunt and Prochazka (Progress in Brain Research152:163-94 (2006)). The FDA-approved use of sacral neuromodulation (SNM)targeting the sacral spinal nerves (INTERSTIM™ therapy of Medtronic, Inc(Minneapolis, Minn.)) has proved partially successful. The Medtronicsystem uses a cylindrical electrode inserted in the S3 sacral foramen (abony tunnel in the pelvis) adjacent to the S3 spinal nerve.Approximately half of screened subjects go on to receive an implant, andonly around 75% of implant recipients experience a ≥50% reduction inleaking episodes (Schmidt, et al. Sacral nerve stimulation for treatmentof refractory urinary urge incontinence, (1999) J Urol. 162(2):352-7).Further, in a multi-centre clinical trial of 98 implanted patients,surgical revision was required in 32.5% of recipients, illustrating thecomplexity of the spinal nerve approach (Van Voskuilen A C, et al.Medium-term experience of sacral neuromodulation by tined leadimplantation. BJU Int 2007;99:107-10; Pham K, et al. Unilateral versusbilateral stage I neuromodulator lead placement for the treatment ofrefractory voiding dysfunction. Neurourol Urodyn 2008; 27:779-81).

Bladder function is comprised of two phases: a filling phase (urinestorage) and a voiding phase (urine evacuation). Despite this biphasicprocess, current artificial electric stimulation protocols do notdifferentiate between the phases, even though the goals of these phasesare diametrically opposed. Instead, it is customary to stimulate with afixed stimulus amplitude, rate and pulse width throughout the day.Advanced features allow for intervening periods of stimulation and nostimulation (cycling), although this is principally to prolong batterylife rather than to specifically target urine storage or voiding(Medtronic INTERSTIM™ Programming Guide), and is not timed with respectto periods of continence (filling or storage) or voiding (micturition orurination).

It would be desirable to provide improved apparatus and methods toprovide for control of bladder function.

SUMMARY OF INVENTION

The pudendal nerve is a somatic nerve (i.e. not autonomic) thatinnervates the urethra, external urethral sphincter, external analsphincter, and perineal skin and carries afferent and efferent signals(FIG. 1 ). Other peripheral nerves innervating the bladder and lowerurinary tract include the hypogastric nerve, an autonomic (sympathetic)nerve that innervates the bladder and urethra and carries afferent andefferent signals (FIG. 1 ), and the pelvic nerve, an autonomic(parasympathetic) nerve that also innervates the bladder and urethra andcarries afferent and efferent signals.

The present inventors have shown herein that stimulation of the pudendalnerve can lead to an increase in bladder capacity. Surprisingly, theinventors further identified that the high level of stimulation requiredto achieve said increase in bladder capacity leads to a decrease inbladder voiding efficiency. This means that the parameters effective atpromoting urine storage and continence led to a reduction in the abilityto void the bladder. Efficient action of both aspects is required fornormal bladder function.

However, as shown herein, stimulation of the pudendal nerve can alsoincrease voiding efficiency if the appropriate stimulation is applied.Based on this observation, the inventors identified that phase-specificpudendal nerve stimulation can provide effective treatment to allaspects of bladder dysfunction. That is, by tailoring the nature of thestimulation applied to the nerve to the ongoing or desired phase of thebladder activity cycle, it is possible to both improve the filling andstorage function of the bladder, and also improve the voiding functionof the bladder.

Thus, the apparatuses and methods provided herein address the problem oftreating bladder dysfunction using electrical apparatuses by applyingphase-specific stimulation to the pudendal nerve in order to achieve theappropriate effect. These apparatuses and methods have the advantage ofproviding greater control of bladder function, whilst not requiringsignificant and potentially dangerous spinal surgery in order toposition apparatuses in signalling contact with these nerves. Inaddition, the apparatuses and methods are able to match more closely thesubject's activities, with the phase-specific stimulation ensuring thatthe appropriate bladder function (filling and storage, or voiding) isaugmented at any given time, rather than the stimulation acting inconflict to the subject (e.g. when the subject wishes to initiatebladder voiding but stimulation is causing storage and preventingvoiding).

Therefore, in a first aspect, the invention provides an apparatus forstimulating neural activity in a pudendal nerve of a subject, theapparatus comprising: at least one transducer configured to apply asignal to said nerve; and a controller coupled to the transducer(s) andcontrolling the signal to be applied by the transducer(s), wherein thecontroller is configured to cause at least one transducer to apply afirst signal that stimulates neural activity in the pudendal nerve toproduce a first physiological response in the subject, and thecontroller is configured to cause at least one transducer to apply asecond signal that stimulates neural activity in the pudendal nerve toproduce a second physiological response in the subject, wherein thefirst physiological response and second physiological response aredifferent.

In a second aspect, the invention provides a method of treating bladderdysfunction in a subject comprising: (i) implanting in the subject anapparatus according to the first aspect; (ii) positioning at least onetransducer of the apparatus in signalling contact with a pudendal nerveof the subject; and (iii) activating the apparatus. In certainembodiments, the first signal and second signal are applied to effectphase-specific stimulation of neural activity in the pudendal nerve.

In a third aspect, the invention provides a method of treating bladderdysfunction in a subject by phase-specific stimulation of neuralactivity in a pudendal nerve of the subject, the method comprising:applying a first signal that stimulates neural activity in the pudendalnerve to produce a first physiological response in the subject, andapplying a second signal that stimulates neural activity in the pudendalnerve to produce a second physiological response in the subject, whereinthe first physiological response and second physiological response aredifferent. In certain embodiments, the first signal is applied during afilling phase and the second signal is applied to trigger micturitionand/or applied during a voiding phase.

In a fourth aspect, the invention provides a use of a neuromodulationapparatus for treating bladder dysfunction in a subject byphase-specific stimulation of neural activity in a pudendal nerve of thesubject.

In a fifth aspect the invention provides a neuromodulation system, thesystem comprising a plurality of apparatuses according to the firstaspect. In such a system, each apparatus may be arranged to communicatewith at least one other apparatus, optionally all apparatuses in thesystem. In certain embodiments, the system is arranged such that, inuse, the apparatuses are positioned to bilaterally stimulate thepudendal nerves of a patient.

In a sixth aspect, the invention provides a pharmaceutical compositioncomprising a compound for treating bladder dysfunction, for use in amethod of treating bladder dysfunction in a subject, wherein the methodis a method according to the second aspect of the invention or accordingto the third aspect of the invention, the method further comprising thestep of administering an effective amount of the pharmaceuticalcomposition to the subject. It is a preferred embodiment that thepharmaceutical composition is for use in a method of treating bladderdysfunction wherein the method comprises applying a signal to a part orall of a pudendal nerve of said patient to stimulate the neural activityof said nerve in the patient, the signal being applied by aneuromodulation apparatus.

In a seventh aspect, the invention provides a pharmaceutical compositioncomprising a compound for treating bladder dysfunction, for use intreating bladder dysfunction in a subject, the subject having anapparatus according to the first aspect implanted. That is, thepharmaceutical composition is for use in treating a subject that has hadan apparatus as described according to the first aspect implanted. Theskilled person will appreciate that the apparatus has been implanted ina manner suitable for the apparatus to operate as described. Use of sucha pharmaceutical composition in a patient having an apparatus accordingto the first aspect implanted will be particularly effective as itpermits a cumulative or synergistic effect as a result of thecombination of the compound for treating bladder dysfunction andapparatus operating in combination.

In preferred embodiments of all aspects of the invention, the subject isa human.

BRIEF DESCRIPTION OF THE DRAWINGS Figures

-   -   FIG. 1 : Schematic drawing showing innervation of the bladder,        internal urethral sphincter (IUS), external urethral sphincter        (EUS) and prostate. Sensory branch of the pudendal nerve (SN),        rectal perineal branch of the pudendal nerve (RP), cranial        sensory branch of the pudendal nerve (CSN), dorsal nerve of the        penis branch of the pudendal nerve (DNP; or clitoris), deep        perineal branch of the pudendal nerve (dPN) and caudal rectal        branch of the pudendal nerve (CR).    -   FIGS. 2A-2C: Schematic drawings showing how apparatuses, devices        and methods according to the invention can be put into effect.    -   FIG. 3 : Electromyographic (EMG) response measured from the        external urethral sphincter in response to electrical        stimulation of the pudendal nerve showing the reflex response        used to determine stimulation intensity threshold (T).    -   FIGS. 4A-4B: Bladder pressure (FIG. 4A) and external urethral        sphincter (EUS) electromygraphic (EMG) activity (FIG. 4B)        recorded in a urethane anesthetized rat following installation        of PGE2 in the bladder and during the delivery of “high        intensity” pudendal nerve stimulation.    -   FIGS. 5A-5B: Summary of changes in bladder capacity (FIG. 5A)        and voiding efficiency (FIG. 5B) in urethane anesthetized rats        following installation of PGE2 in the bladder and during the        delivery of “high intensity” pudendal nerve stimulation. PGE2        reduces bladder capacity and this effect is reversed by “high        intensity” pudendal nerve stimulation. However “high intensity”        pudendal nerve stimulation reduced voiding efficiency.    -   FIGS. 6A-6B: State-dependent switching of stimulation intensity        increases both bladder capacity and voiding efficiency in        urethane anesthetized rats following installation of PGE2 in the        bladder. FIG. 6A: No stimulation: the bladder capacity was 0.49        ml and voiding efficiency was 56%. “High intensity” pudendal        nerve stimulation increased bladder capacity to 0.63 ml, but had        only a marginal effect on voiding efficiency (=62%). FIG. 6B:        Phase-specific stimulation: Switching stimulation intensity from        “high” during the filling phase to “low” during the voiding        phase increased both bladder capacity (=0.67 ml) and voiding        efficiency (=82%).    -   FIGS. 7A-7D: Example cystometrogram trials in cats during        distention evoked voiding (FIG. 7A) and distention evoked        voiding with unilateral compound pudendal stimulation (FIGS.        7B-7D). FIG. 7A: Bladder pressure during a distention evoked        trial resulting in a bladder capacity (BC) of 9.1 ml and voiding        efficiency (% VE) of 29%. FIG. 7B: Bladder pressure during        pudendal stimulation at 50 μA at 10 Hz resulting in a BC of 8.5        ml and a VE of 30%. FIG. 7C: Bladder pressure during pudendal        stimulation at 60 μA at 10 Hz resulting in a BC of 8.5 ml and a        VE of 13%. FIG. 7D: Bladder pressure during pudendal stimulation        at 200 μA at 20 Hz resulting in a BC of 20 ml and a VE of 20%.        Stimulation is turned on at the start of the cystometrogram and        is subsequently turned off after the end of the void. Each        stimulation pulse was biphasic with a 100 us duration for each        phase.    -   FIGS. 8A-8G: Example cystometrogram trials in cats during        distention evoked voiding (FIGS. 8A-8C) and distention evoked        voiding with unilateral phasic stimulation (FIGS. 8D-8F) of the        pudendal somatic motor branch (DPeriN). FIG. 8A: Bladder        pressure (top) and voided volume (bottom) during a distention        evoked trial. FIG. 8B: An expanded trace from FIG. 8A showing        bladder pressure (top) and voided volume during the bladder        contraction. FIG. 8C: An expanded view of the bladder pressure        demonstrating the absence of high frequency oscillations (HFOs)        during a void event. (FIG. 8D: Bladder pressure (top) and voided        volume (bottom) during DPeriN phasic stimulation (red trace).        DPeriN stimulation is turned on during a voiding event and is        subsequently turned off after the end of the void. FIG. 8E: An        expanded trace from FIG. 8D showing bladder pressure (top) and        voided volume during the bladder contraction. DPeriN phasic        stimulation (red trace) elicited HFOs during stimulation. FIG.        8F: An expanded view of the bladder pressure during phasic        stimulation. Oscillations in bladder pressure follow each        stimulation burst. FIG. 8G: Example of urethral pressure in        response to 2 Hz bursts of DPeriN stimulation. Urethral pressure        recorded during bladder empty conditions. The inter-pulse        frequency was 40 Hz, and each burst was 100 ms in duration.    -   FIGS. 9A-9C: Average bladder contraction amplitude (FIG. 9A),        bladder contraction area under the curve (AUC) (FIG. 9B), and        voiding efficiency (FIG. 9C) in cat during voiding trials        between distention evoked control and pudendal somatic motor        branch (DPeriN) 2 Hz burst stimulation during intact, motor        transection, and complete (sensory and motor) transection        conditions. FIG. 9A: Bladder contraction amplitude evoked by        artificial phasic stimulation was significantly larger than        distention controls in both the intact and bilateral pudendal        motor transection conditions. Phasic stimulation evoked increase        in bladder contraction amplitude was abolished after complete        bilateral pudendal transection (motor and sensory). FIG. 9B:        Artificial phasic stimulation did not significantly decrease        bladder contraction AUC compared to distention controls in        intact, bilateral pudendal motor transection, and complete        bilateral pudendal transection (motor and sensory) conditions.        FIG. 9C: Artificial phasic stimulation significantly increased %        voiding efficiency compared to distention controls in both the        intact and bilateral pudendal motor transection conditions.        Phasic stimulation evoked increase in % voiding efficiency was        abolished after complete bilateral pudendal transection (motor        and sensory).

The terms as used herein are given their conventional definition in theart as understood by the skilled person, unless otherwise defined below.In the case of any inconsistency or doubt, the definition as providedherein should take precedence.

As used herein, “application of a signal” may equate to the transfer ofenergy in a suitable form to carry out the intended effect of thesignal. That is, application of a signal to a nerve or nerves may equateto the transfer of energy to (or from) the nerve(s) to carry out theintended effect. For example, the energy transferred may be electrical,mechanical (including acoustic, such as ultrasound), electromagnetic(e.g. optical), magnetic or thermal energy. It is noted that applicationof a signal as used herein does not include a pharmaceuticalintervention.

As used herein, “transducer” is taken to mean any element of applying asignal to the nerve or plexus, for example an electrode, diode, Peltierelement or ultrasound actuator.

As used herein, “neural activity” of a nerve is taken to mean thesignalling activity of the nerve, for example the amplitude, frequencyand/or pattern of action potentials in the nerve.

“Modulation of neural activity”, as used herein, is taken to mean thatthe signalling activity of the nerve is altered from the baseline neuralactivity—that is, the signalling activity of the nerve in the subjectprior to any intervention. Such modulation may increase, inhibit, block,or otherwise change the neural activity compared to baseline activity.

“Stimulation of neural activity” as used herein may be an increase inthe total signalling activity of the whole nerve, or that the totalsignalling activity of a subset of nerve fibres of the nerve isincreased, compared to baseline neural activity in that part of thenerve. In a preferred embodiment, the modulation of neural activity isan increase in the signalling activity of the sensory fibres of thenerve, optionally a selective increase in the signalling activity of thesensory fibres of the nerve. A selective increase in neural activity ofthe sensory fibres causes a preferential increase in neural activity inthe sensory fibres compared to any increase in neural signalling in themotor nerve fibres of the pudendal nerve. In a preferred alternativeembodiment, the modulation of neural activity is an increase in thesignalling activity of the motor fibres of the nerve, optionally aselective increase in the signalling activity of the motor fibres of thenerve. A selective increase in neural activity of the motor fibrescauses a preferential increase in neural activity in the motor fibrescompared to any increase in neural signalling in the sensory nervefibres of the pudendal nerve.

“Modulation of neural activity” may also be an alteration in the patternof action potentials. It will be appreciated that the pattern of actionpotentials can be modulated without necessarily changing the overallfrequency. For example, modulation of the neural activity may be suchthat the pattern of action potentials is altered to more closelyresemble a healthy state rather than a disease state—i.e. to moreclosely resemble the pattern in a healthy individual.

“Phase-specific” or “phase-specific stimulation” are each taken to meanthat a different stimulation is applied depending on the ongoing and/ordesired phase of the normal bladder activity cycle. The bladder activitycycle is characterised by a filling phase (also referred to as a storagephase), followed by a triggering of the micturition, followed by avoiding phase (also referred to as the micturition phase). A normalbladder activity cycle is a bladder activity cycle characteristic of ahealthy individual.

The “ongoing phase” of bladder activity is the phase of the bladderactivity cycle occurring at a particular given time. That a subject isin a given phase of the cycle can be indicated by a physiologicalparameter relevant to bladder activity, for example bladder pressure.For example, that a subject is in the filling phase may be indicated byincreasing bladder pressure, or a sustained bladder pressure indicatingthat the bladder is at least partially filled. Triggering of micturitionmay be indicated by a sharp increase in bladder pressure. Otherphysiological parameters relevant to bladder activity include nerveactivity in the pudendal nerve, nerve activity in the hypogastric nerve,nerve activity in the pelvic nerve, muscle activity in the bladderdetrusor muscle, muscle activity in the internal urethral sphincter,muscle activity in the external urethral sphincter (EUS), muscleactivity in the external anal sphincter.

The “desired phase” of the bladder activity cycle is the phase of thebladder activity cycle of which the subject is desirous. The desiredphase may depend on the behaviour of the subject, for example whetherthey are sleeping, at exercise, at work, etc. Similarly, the desiredphase may depend on perceived levels of urinary comfort. For example,the subject may perceive discomfort due to the sensation of having afull bladder, and therefore be desirous of triggering micturition.

It will be appreciated that phase-specific stimulation can take intoaccount both ongoing and desirous phases of the bladder activity cycle.For example, a first stimulating signal may be applied (e.g. to increasebladder capacity) during a filling phase indicated by increasing bladderpressure, and a second stimulating signal may be applied when thesubject is desirous of beginning micturition (e.g. to triggermicturition), or during a voiding phase as indicated by a change inmuscle activity in the EUS (e.g. to increase voiding efficiency).

As used herein, a “healthy individual” or “healthy subject” is anindividual not exhibiting any disruption or perturbation of normalbladder activity.

As used herein, “bladder dysfunction” is taken to mean that the patientor subject is exhibiting disruption of bladder function compared to ahealthy individual. Bladder dysfunction may be characterised by symptomssuch as nocturia, increased urinary retention, increased incontinence,increased urgency of urination or increased frequency of urinationcompared to a healthy individual. Bladder dysfunction includesconditions such as overactive bladder (OAB), neurogenic bladder, stressincontinence, and chronic urinary retention.

As used herein, an “improvement in a measurable physiological parameter”is taken to mean that for any given physiological parameter, animprovement is a change in the value of that parameter in the subjecttowards the normal value or normal range for that value—i.e. towards theexpected value in a healthy individual.

For example, in a subject with bladder dysfunction, an improvement in ameasurable parameter may be: a reduction in number of incontinenceepisodes, a decrease in urgency of urination, a decrease in frequency ofurination, an increase in bladder capacity, an increase in bladdervoiding efficiency, and/or a change in external urethral sphincter (EUS)activity towards that of a healthy individual, assuming the subject isexhibiting abnormal values for the respective parameter.

As used herein, a physiological parameter is not affected by modulationof the neural activity if the parameter does not change as a result ofthe modulation from the average value of that parameter exhibited by thesubject or subject when no intervention has been performed—i.e. it doesnot depart from the baseline value for that parameter.

The skilled person will appreciate that the baseline for any neuralactivity or physiological parameter in an individual need not be a fixedor specific value, but rather can fluctuate within a normal range or maybe an average value with associated error and confidence intervals.Suitable methods for determining baseline values would be well known tothe skilled person.

As used herein, a measurable physiological parameter is detected in asubject when the value for that parameter exhibited by the subject atthe time of detection is determined. A detector is any element able tomake such a determination.

A “predefined threshold value” for a physiological parameter is thevalue for that parameter where that value or beyond must be exhibited bya subject or subject before the intervention is applied. For any givenparameter, the threshold value may be defined as a value indicative of apathological state (e.g. the subject is experiencing abnormal retentionof urine) or a particular physiological state (e.g. the subject having afull bladder), or a particular behavioural state (e.g. the subjectwishes to being voiding/micturition). Examples of such predefinedthreshold values include: bladder pressure abnormal compared to ahealthy individual, bladder pressure indicative of bladder at or nearcapacity, abnormal peripheral nerve activity (for example, pudendalnerve, hypogastric nerve or pelvic nerve) compared to a healthyindividual, abnormal EUS activity compared to a healthy individual (forinstance an increase in EUS activity). Such a threshold value for agiven physiological parameter is exceeded if the value exhibited by thesubject is beyond the threshold value—that is, the exhibited value is agreater departure from the normal or healthy value for that parameterthan the predefined threshold value.

The measurable physiological parameter may comprise an action potentialor pattern of action potentials in one or more nerves of the subject,wherein the action potential or pattern of action potentials isassociated with bladder dysfunction. Suitable nerves in which to detectan action potential or pattern of action potentials include a pudendalnerve, a pelvic nerve and/or a hypogastric nerve. In a particularembodiment, the measurable physiological parameter comprises the patternof action potentials in the pudendal nerve. The measureablephysiological parameter may be muscle electromyographic activity,wherein the electromyographic activity is indicative of the level ofactivity in the muscle. Such activity could typically be measured fromthe bladder detrusor muscle, the internal urethral sphincter, theexternal urethral sphincter, and the external anal sphincter.

Treatment of bladder dysfunction, as used herein may be characterised byany one or more of a reduction in number of incontinence episodes, adecrease in urgency of urination, a decrease in frequency of urination,an increase bladder capacity, an increase in bladder voiding efficiency,a decrease in urinary retention, a change in external urethral sphincter(EUS) activity towards that of a healthy individual, and/or a change inthe pattern of action potentials or activity of the pelvic nerve,pudendal nerve or hypogastric nerve towards that of a healthyindividual. Treatment of bladder function may be characterised by acombination of an increase in bladder capacity during filling periodsand an increase in voiding efficiency for voiding periods.

A “neuromodulation apparatus” as used herein is an apparatus configuredto modulate the neural activity of a nerve. Neuromodulation devices asdescribed herein comprise at least one transducer capable of effectivelyapplying a signal to a nerve. In those embodiments in which theneuromodulation apparatus is at least partially implanted in thesubject, the elements of the apparatus that are to be implanted in thesubject are constructed such that they are suitable for suchimplantation.

As used herein, “implanted” is taken to mean positioned within thesubject's body. Partial implantation means that only part of theapparatus is implanted—i.e. only part of the apparatus is positionedwithin the subject's body, with other elements of the apparatus externalto the subject's body. Wholly implanted means that the entire apparatusis positioned within the subject's body. For the avoidance of doubt, theapparatus being “wholly implanted” does not preclude additionalelements, independent of the apparatus but in practice useful for itsfunctioning (for example, a remote wireless charging unit or a remotewireless manual override unit), being independently formed and externalto the subject's body.

DETAILED DESCRIPTION

In accordance with a first aspect of the invention there is provided anapparatus for stimulating neural activity in a pudendal nerve of asubject, the apparatus comprising: a transducer configured to apply asignal to said nerve; and a controller coupled to the transducer andcontrolling the signal to be applied by the transducer, such that thecontroller is configured to cause a first signal to be applied whichstimulates neural activity in the pudendal nerve to produce a firstphysiological response in the subject, and the controller is configuredto cause a second signal to applied which stimulates neural activity inthe pudendal nerve to produce a second physiological response in thesubject, wherein the first and second physiological responses aredifferent.

In certain embodiments, the first and second physiological responsesproduced in the subject as a result of the first and second signal areeach independently selected from one or more of: an increase in bladdercapacity, a decrease in the sensation of urgency, a decrease inincontinence, an increase in bladder voiding efficiency, a decrease inurinary retention and/or a change in external urethral sphincter (EUS)activity towards that of a healthy individual. In certain embodiments,the physiological response produced by the first signal is an increasein bladder capacity and the physiological response produced by thesecond signal is an increase in voiding efficiency.

In certain embodiments, the controller is configured to apply the signalin a phase-specific manner. In certain embodiments, the controllercauses the first signal to be applied when the subject is in the storagephase of the micturition cycle and causes the second signal to beapplied to trigger the micturition phase. In certain embodiments thecontroller causes the first signal to be applied when the subject is inthe storage phase of the micturition cycle and causes the second signalto be applied when the subject is in the micturition phase of the cycle.In certain such embodiments, the second signal is applied both totrigger micturition and during the subsequent voiding phase. In certainsuch embodiments, application of the first signal results in an increasein bladder capacity, and application of the second signal results in anincrease in voiding efficiency.

In certain embodiments the apparatus comprises a first transducer and asecond transducer. In certain such embodiments, the controller isconfigured to cause the first transducer to apply the first signal, andthe second transducer to apply the second signal. In certainembodiments, the controller is configured to cause the first and secondtransducers to each apply the first and second signals.

In certain embodiments, the first and second transducers may beconfigured to apply a signal to same pudendal nerve. In certainalternative embodiments, the first and second transducers may beconfigured such that a signal may be applied bilaterally—that is, thefirst transducer is configured to apply a signal to the left pudendalnerve, and the second transducer is configured to apply a signal to theright transducer. In such embodiments, the first and second signal mayeach be configured to apply both the first and second signals, or thefirst signal may be applied by the first transducer to the left pudendalnerve and the second signal may be applied by the second transducer tothe right pudendal nerve.

In the passages below, the described embodiments of the signal applyequally and independently to the first and second signals unlessotherwise specified.

In certain embodiments, the signal selectively stimulates neuralactivity in the sensory fibres of the pudendal nerve. A signalselectively stimulates the neural activity of the sensory fibres of thepudendal nerve if that signal does not modulate the neural activity ofthe motor fibres of the nerve. In certain alternative embodiments, thesignal increases signalling activity of the motor fibres of the nerve,optionally selectively increases the signalling activity of the motorfibres of the nerve.

In certain embodiments, the signal which the transducer is configured toapply is of a modality selected from an electrical signal, an opticalsignal, an ultrasonic signal, and a thermal signal. That is, eachtransducer may be configured to apply a different modality of signal.Alternatively, in certain embodiments each transducer is configured toapply the same modality of signal.

In certain embodiments, each transducer may be comprised of one or moreelectrodes, one or more photon sources, one or more ultrasoundtransducers, one more sources of heat, or one or more other types oftransducer arranged to put the signal into effect.

In certain embodiments, the transducer is an electrode and the signalapplied by the transducer is an electrical signal, for example a voltageor current. In certain such embodiments, the transducer is a wireelectrode or cuff electrode, for example a bipolar or tripolar cuffelectrode.

In certain such embodiments the signal applied comprises a directcurrent (DC) waveform, or an alternating current (AC) waveform, or botha DC and an AC waveform.

In certain embodiments the signal comprises an AC waveform having afrequency of 0.1-500 Hz, optionally 0.25-100 Hz, optionally 0.5-50 Hz,optionally 1-30 Hz, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28. 29, or30 Hz, optionally 1, 10, 20 or 30 Hz. In certain embodiments the firstsignal comprises an AC waveform having a frequency of 1-50 Hz,optionally 5-30 Hz, optionally 10-25 Hz, optionally 15-20 Hz, optionally20 Hz. In certain embodiments the second signal comprises an AC waveformhaving a frequency of 0.5-50 Hz, optionally 0.5-20 Hz, optionally 1-10Hz, optionally 1 Hz.

In certain embodiments, the signal is a charge-balanced AC waveform. Incertain embodiments, the AC waveform is a biphasic waveform, optionallya charge-balanced biphasic waveform. In certain such embodiments, thewaveform may be symmetrical or asymmetrical. In certain suchembodiments, each phase of the biphasic waveform has a phase durationfrom 0.005 ms to 2 ms, optionally 0.01 to 1 ms, optionally 0.05 to 0.5ms, optionally 0.05 to 0.2 ms, optionally 0.1 ms. In certainembodiments, each phase of a biphasic waveform is of equal duration. Incertain alternative embodiments, each phase is of a different duration.

The AC waveform may be selected from sinusoidal, triangular, square or acomplex waveform.

Typically, effective induction of the intended physiological effectrequires the selection of appropriate stimulation parameters.Stimulation parameters include the stimulation pulseamplitude/intensity, the stimulation pulse duration, and stimulationfrequency.

Relative stimulation pulse intensity can be expressed as multiples (0.1,0.8, 1, 2, 5, etc.) of “T”. “T” is the threshold stimulation intensityrequired to evoke a response. “T” may be the threshold stimulationintensity required to evoke a motor response. In humans, for example,“T” may be defined as the threshold required to evoke a foot or toetwitch, pelvic floor bellowing, pelvic floor contraction (for exampleanal wink), or a reflex electromyogram (EMG) response in the externalurethral sphincter (EUS). Alternatively, “T” may be the thresholdstimulation intensity required to evoke a sensory response, for examplea response perceived by the patient. Preferably, “T” is the thresholdstimulation intensity required to evoke a reflex electromyogram (EMG)response in the external urethral sphincter (EUS).

By way of example, T may be determined as follows: a low frequencyelectrical signal, typically 1 Hz, is applied and the intensity ofstimulation is increased (either by increasing the voltage or thecurrent of the signal, preferably the current) until the pudendal nervestimulation pulse produces a reflex EMG response in the EUS. Thisstimulation intensity is designated T. The absolute thresholdstimulation intensity may vary across individuals, and subsequentexperimental or therapeutic intensities are designated as multiples of Tto provide equivalent relative stimulation intensities.

The desired stimulation intensity (i.e. the desired multiple ofthreshold intensity “T”) can be achieved through controlled variation ofthe current or voltage of the signal, preferably the current.

In certain embodiments the electrical signal has an amplitude value offrom 0.1 T to 15.0 T, where T is a threshold obtained through empiricalmeasurement of the threshold for the stimulation signal to evoke areflex response in the external urethral sphincter or external analsphincter, following application of stimulus to the pudendal nerve. Incertain embodiments, the electrical signal has a T value of 0.1 T-15.0T, 0.5T-10 T, 0.5 T-2.0 T, 5.0 T-10 T.

In certain preferred embodiments, the signal is an electrical signalcomprising an AC waveform of 400 μA 20 Hz, or 50 μA 1 Hz.

In certain embodiments, the first signal is a high amplitude electricalsignal and induces an increase in bladder capacity, and the secondsignal is a low amplitude electrical signal and induces an increase invoiding efficiency. A high amplitude signal is an electrical signal of2.0-10 T, optionally 5-10 T, optionally 8-10 T, optionally 2, 3, 4, 5,6, 7, 8, 9, or 10 T and/or of 1-50 Hz. A low amplitude electrical signalis a signal of 0.5-3.0 T, optionally 1-3 T, optionally 2-3 T, optionally0.5 T, 1 T, 1.5 T, 2 T, 2.5 T, or 3 T and/or of 1-50 Hz. In certain suchembodiments, the low amplitude signal has a T value lower than the Tvalue of the high amplitude signal.

In certain embodiments wherein the signal applied by the one or moretransducers is a thermal signal, the signal reduces the temperature ofthe nerve (i.e. cools the nerve). In certain alternative embodiments,the signal increases the temperature of the nerve (i.e. heats thenerve). In certain embodiments, the signal both heats and cools thenerve.

In those embodiments in which the signal applied by the one or moretransducers is a thermal signal, at least one of the one or moretransducers is configured to apply a thermal signal. In certain suchembodiments, all the transducers are configured to apply a thermalsignal, optionally the same thermal signal.

In certain embodiments, one or more of the one or more transducerscomprise a Peltier element configured to apply a thermal signal,optionally all of the one or more transducers comprise a Peltierelement. In certain embodiments, one or more of the one or moretransducers comprise a laser diode configured to apply a thermal signal,optionally all of the one or more transducers comprise a laser diodeconfigured to apply a thermal signal (e.g. a diode configured to emitinfrared radiation). In certain embodiments, one or more of the one ormore transducers comprise an electrically resistive element configuredto apply a thermal signal, optionally all of the one or more transducerscomprise an electrically resistive element configured to apply a thermalsignal.

In certain embodiments the signal applied by the one or more transducersis a mechanical signal, optionally an ultrasonic signal. In certainalternative embodiments, the mechanical signal applied by the one ormore transducers is a pressure signal.

In certain embodiments the signal applied by the one or more transducersis an electromagnetic signal, optionally an optical signal. In certainsuch embodiments, the one or more transducers comprise a laser and/or alight emitting diode configured to apply the optical signal. In someembodiments, the apparatus further comprises a fibre optic interfaceconfigured to apply said signal from said one or more of the transducersto said at least one nerve.

In certain embodiments, the apparatus further comprises a detector todetect one or more physiological parameters in the subject. Such adetector may be configured to detect one physiological parameter or aplurality of physiological parameters The detected physiologicalparameter(s) are selected from nerve activity in the pudendal nerve,nerve activity in the hypogastric nerve, nerve activity in the pelvicnerve, muscle activity in the bladder detrusor muscle, muscle activityin the internal urethral sphincter, muscle activity in the externalurethral sphincter, muscle activity in the external anal sphincter, andbladder pressure.

In such embodiments, the controller is coupled to the detectorconfigured to detect a physiological parameter, and causes the firstsignal to be applied when the physiological parameter is detected to bemeeting or exceeding a first predefined threshold value, and causes thesecond signal to be applied when the physiological parameter is detectedto be meeting or exceeding a second predefined threshold value.

It will be appreciated that any two or more of the indicatedphysiological parameters may be detected in parallel or consecutively.For example, in certain embodiments, the controller is coupled to adetector or detectors configured to detect the pattern of actionpotentials in the pudendal nerve at the same time as the bladderpressure in the subject.

In addition or as an alternative to a detector, the apparatus maycomprise an input element. In such embodiments, the input element allowsthe subject to enter data regarding their behaviour and/or desires. Forexample, the input element may allow the subject to enter that theydesire to begin bladder voiding (i.e. intend to begin urinating). Insuch embodiments, the controller is configured to cause a signal to beapplied that produces a physiological response appropriate to the datainput—for example, in the case of the intention to urinate beingindicated, the signal may increase voiding efficiency. By way of furtherexample, the input element may also allow the subject to enter dataindicative of behaviour in which storage phase is appropriate (e.g.sleeping or following urination, where it is desirous to promotestorage). In response to such data being entered via the input element,the controller causes a signal to be applied that produces aphysiological response appropriate for improved storage, for exampleincreased bladder capacity.

The input element may be connected directly to the controller, or be inwireless communication as a remote component, for example a componentcarried by the subject. Such arrangements and configurations arediscussed in further detail below.

According to the invention, stimulation in neural activity as a resultof applying the signal is an increase in neural activity in the nerve towhich the signal is applied. That is, in such embodiments, applicationof the signal results in the neural activity in at least the sensoryfibres of at least part of the nerve being increased compared to thebaseline neural activity in that part of the nerve. In certainembodiments, neural activity is increased across the whole nerve. Incertain preferred embodiments, neural activity is selectively stimulatedin the sensory fibres of the pudendal nerve to which the signal isapplied.

In certain embodiments, the controller causes each signal to be appliedfor a set time period, such that a stimulation cycle is defined. In suchembodiments, the controller is configured to apply the first signal fora first time period and the second signal for a second time period. Incertain such embodiments, the first signal produces a physiologicalresponse appropriate to aid normal bladder filling and storage (forexample increased bladder capacity) and the first time period is of aduration appropriate for a healthy, comfortable storage phase, and thesecond signal produces a physiological response appropriate to aidvoiding (for example, increased voiding efficiency) and the second timeperiod is of a duration appropriate for a healthy voiding phase.

In certain such embodiments, the controller is configured not to causeany signal to be applied for a third time period following the secondtime period—i.e. after a signal that promotes voiding. An advantage ofthe controller being so configured is that battery life of the apparatuscan be prolonged.

In certain embodiments, the first, second (and third when present) timeperiods run consecutively and repeat cyclically.

In certain embodiments, the duration of the each time period isindependently selected. In certain such embodiments, the duration ofeach time period is selected from 5 seconds (5 s) to 24 hours (24 h), 30s to 12 h, 1 min to 12 h, 5 min to 8 h, 5 min to 6 h, 10 min to 6 h, 10min to 4 h, 30 min to 4 h, 1 h to 4 h. In certain embodiments, theduration of each of the first, second, third and fourth time periods is5 s, 10 s, 30 s, 60 s, 2 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h,12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h,24 h. In certain embodiments, the duration of each time period isselected from 0.05 seconds (0.05 s) to 5 second (5 s), optionally 0.1 sto 2 s, optionally 0.1 s to 1 s, optionally 0.2 s to 0.8 s, optionally0.3 s to 0.7 s, optionally 0.4 s to 0.6 s, optionally 0.5 s. Forexample, in certain such embodiments, the signal may be applied for aperiod of 0.1 ms every 0.5 s (that is, with a period of 0.5 s).

In certain embodiments, the controller is configured to cause the signalto be applied for a specific amount of time per day. In certain suchembodiments, each signal may be applied for 10 min, 20 min, 30 min, 40min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22h, 23 h per day. In certain embodiments, the apparatus is suitable forat least partial implantation into the subject. In certain suchembodiments, the apparatus is suitable to be fully implanted in thesubject.

In certain embodiments, the apparatus further comprises one or morepower supply elements, for example a battery, and/or one or morecommunication elements.

In a second aspect, the invention provides a method for treating bladderdysfunction in a patient, the method comprising implanting an apparatusaccording to the first aspect, positioning a transducer of the apparatusin signalling contact with a pudendal nerve of the subject, andactivating the apparatus. In such embodiments, the transducer is insignalling contact with the nerve when it is positioned such that asignal can be effectively applied to the nerve. The apparatus isactivated when the apparatus is in an operating state such that thesignal will be applied as determined by the controller.

In such embodiments, the controller causes the transducer positioned insignalling contact with a pudendal nerve to apply a first signal so asto produce a first physiological response in the subject, and thecontroller is configured to cause a second signal to applied whichstimulates neural activity in the pudendal nerve to produce a secondphysiological response in the subject, wherein the first and secondphysiological responses are different.

In certain embodiments, the first signal and second signal are appliedto effect phase-specific stimulation. In certain embodiments, the firstsignal is applied during a filling phase and the second signal isapplied to trigger micturition. In certain embodiments the first signalis applied during a filling phase and the second signal applied during avoiding phase. In certain such embodiments, the second signal is appliedboth to trigger micturition and during the subsequent voiding phase. Incertain embodiments, the first and second physiological responsesproduced in the subject as a result of the first and second signal beingapplied are each independently selected from one or more of: an increasein bladder capacity, an increase in bladder voiding efficiency, adecrease in urinary retention, a decrease in the sensation of urgency, adecrease in incontinence and/or a change in external urethral sphincter(EUS) activity towards that of a healthy individual. In certainembodiments, the physiological response produced by the first signal isan increase in bladder capacity and the physiological response producedby the second signal is an increase in voiding efficiency.

In certain embodiments, the method comprises implanting an apparatusaccording to the first aspect having a first transducer and a secondtransducer, and positioning the transducers bilaterally—that is, onetransducer in signalling contact with the left pudendal nerve, and onetransducer in signalling contact with the right pudendal nerve. In suchembodiments, the controller may cause each transducer to apply eitherthe first signal or the second signal, or may cause the first transducerto apply the first signal and the second transducer to apply the secondsignal.

In certain embodiments, the method is a method for treating overactivebladder or neurogenic bladder or detrusor hyperactivity with impairedcontractility (DHIC).

Implementation of all aspects of the invention (as discussed both aboveand below) will be further appreciated by reference to FIGS. 2A-2C.

FIGS. 2A-2C show how the invention may be put into effect using one ormore neuromodulation apparatuses which are implanted in, located on, orotherwise disposed with respect to a subject in order to carry out anyof the various methods described herein. In this way, one or moreneuromodulation apparatuses can be used to treat bladder dysfunction ina subject, by modulating neural activity in a pudendal nerve.

In FIG. 2A a separate neuromodulation apparatus 100 is provided forunilateral neuromodulation, although as discussed above and below anapparatus could be provided for bilateral neuromodulation (100, FIG. 2Band 2C). Each such neuromodulation apparatus may be fully or partiallyimplanted in the subject, or otherwise located, so as to provideneuromodulation of the respective nerve or nerves. FIG. 2A alsoschematically shows in the cutaway components of one of theneuromodulation apparatuses 100, in which the apparatus comprisesseveral elements, components or functions grouped together in a singleunit and implanted in the subject. A first such element is a transducer102 which is shown in proximity to a pudendal nerve 90 of the subject.The apparatus may optionally further comprise further transducers (notshown) implanted proximally to the other pudendal nerve. Alternatively,the other pudendal nerve may be provided with a separate apparatus 100(not shown). The transducer 102 may be operated by a controller 104. Theapparatus may comprise one or more further elements such as acommunication element 106, a detector 108, a power supply element 110and so forth. Each neuromodulation apparatus 100 may operateindependently, or may operate in communication with each other, forexample using respective communication elements 106.

Each neuromodulation apparatus 100 may carry out the requiredphase-specific stimulation in response to one or more control signals.Such a control signal may be provided by the controller 104 according toan algorithm independently, in response to output of one or moredetector elements 108, and/or in response to communications from one ormore external sources (for example an input element) received using thecommunications element. As discussed herein, the detector(s) could beresponsive to a variety of different physiological parameters.

FIG. 2B illustrates some ways in which the apparatus of FIG. 2A may bedifferently distributed. For example, in FIG. 2B the neuromodulationapparatuses 100 comprise transducers 102 implanted proximally to apudendal nerve 90, but other elements such as a controller 104, acommunication element 106 and a power supply 110 are implemented in aseparate control unit 130 which may also be implanted in, or carried bythe subject. The control unit 130 then controls the transducers in bothof the neuromodulation apparatuses via connections 132 which may forexample comprise electrical wires and/or optical fibres for deliveringsignals and/or power to the transducers.

In the arrangement of FIG. 2B one or more detectors 108 are locatedseparately from the control unit, although one or more such detectorscould also or instead be located within the control unit 130 and/or inone or both of the neuromodulation apparatuses 100. The detectors may beused to detect one or more physiological parameters of the subject, andthe controller or control unit then causes the transducers to apply thefirst or second signal in response to the detected parameter(s), forexample only when a detected physiological parameter meets or exceeds apredefined threshold value. Physiological parameters which could bedetected for such purposes nerve activity in the pudendal nerve, nerveactivity in the hypogastric nerve, nerve activity in the pelvic nerve,muscle activity in the bladder detrusor muscle, muscle activity in theinternal urethral sphincter, muscle activity in the external urethralsphincter, muscle activity in the external anal sphincter, and bladderpressure.

A variety of other ways in which the various functional elements couldbe located and grouped into the neuromodulation apparatuses, a controlunit 130 and elsewhere are of course possible. For example, one or moresensors of FIG. 2B could be used in the arrangement of FIGS. 2A or 2C orother arrangements.

FIG. 2C illustrates some ways in which some functionality of theapparatus of FIGS. 2A or 2B is provided not implanted in the subject.For example, in FIG. 2C an external power supply 140 is provided whichcan provide power to implanted elements of the apparatus in waysfamiliar to the skilled person, and an external controller 150 providespart or all of the functionality of the controller 104, and/or providesother aspects of control of the apparatus, and/or provides data readoutfrom the apparatus, and/or provides a data input element 152. The datainput facility could be used by a subject or other operator in variousways, for example to input data relating to the behaviour of the subjectand/or their desires (e.g. to begin urination).

Each neuromodulation apparatus may be adapted to carry out thephase-specific stimulation required using one or more physical modes ofoperation which typically involve applying a first signal and a secondsignal to a pudendal nerve or subcomponents of a pudendal nerve (e.g.sensory fibres or motor fibres), such signals typically involving atransfer of energy to (or from) the nerve(s). As already discussed, suchmodes may comprise modulating the nerve or nerves using an electricalsignal, an optical signal, an ultrasound or other mechanical signal, athermal signal, a magnetic or electromagnetic signal, or some other useof energy to carry out the required stimulation. Preferably themodulation comprises selectively stimulating neural activity in thesensory fibres of the nerve or nerves. Alternatively, the signalincreases signalling activity of the motor fibres of the nerve,optionally selectively increases the signalling activity of the motorfibres of the nerve. The transducer 90 illustrated in FIG. 2A could becomprised of one or more electrodes, one or more photon sources, one ormore ultrasound transducers, one more sources of heat, or one or moreother types of transducers arranged to put the required neuromodulationinto effect. The neuromodulation apparatus may comprise at least twotransducers arranged in order for each to stimulate a differentsubcomponent of the pudendal nerve, for example a first transducerarranged to stimulate the sensory fibres and a second transducerarranged to stimulate the motor fibres.

The neural modulation apparatus may be arranged to stimulate (i.e.increase or induce) neural activity of a pudendal nerve, by using thetransducer(s) to apply a voltage or current, for example a directcurrent (DC) waveform, or an AC waveform, or both. In such embodiments,the transducer is an electrode, such as a wire electrode or cuffelectrode, for example a bipolar or tripolar cuff electrode.

The apparatus may be arranged to use the transducer(s) to apply anelectrical signal comprising an AC waveform having a frequency of0.1-500 Hz, optionally 0.25-100 Hz, optionally 0.5-50 Hz, optionally1-30 Hz, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28. 29, or 30 Hz,optionally 1, 10, 20 or 30 Hz. In certain embodiments the first signalcomprises an AC waveform having a frequency of 1-50 Hz, optionally 5-30Hz, optionally 10-25 Hz, optionally 15-20 Hz, optionally 20 Hz. Incertain embodiments the second signal comprises an AC waveform having afrequency of 0.5-50 Hz, optionally 0.5-20 Hz, optionally 1-10 Hz,optionally 1 Hz.

In certain embodiments, the signal is a charge-balanced AC waveform. Incertain embodiments, the AC waveform is a biphasic waveform, optionallya charge-balanced biphasic waveform. In certain such embodiments, thewaveform may be symmetrical or asymmetrical. In certain suchembodiments, each phase of the biphasic waveform has a phase durationfrom 0.005 ms to 2 ms, optionally 0.01 to 1 ms, optionally 0.05 to 0.5ms, optionally 0.05 to 0.2 ms, optionally 0.1 ms. In certainembodiments, each phase of a biphasic waveform is of equal duration. Incertain alternative embodiments, each phase is of a different duration.

The AC waveform may be selected from sinusoidal, triangular, square or acomplex waveform.

In certain embodiments each electrical signal has an amplitude of from0.1 T to 15 T, where “T” is the intensity of stimulation at which, for agiven frequency (typically 1 Hz), a reflex EMG response in the EUS isproduced. The skilled person would be readily able to determine theappropriate value of T in any given subject.

In certain embodiments, the electrical signal has a T value of 0.1T-15.0 T, 0.5 T-10 T, 0.5 T-2.0 T, or 5.0 T-10 T.

In certain embodiments, the first signal is a high amplitude electricalsignal and induces an increase in bladder capacity, and the secondsignal is a low amplitude electrical signal and induces an increase invoiding efficiency. A high amplitude signal is an electrical signal of2.0-10 T, optionally 5-10 T, optionally 8-10 T, optionally 2, 3, 4, 5,6, 7, 8, 9, or 10 T and/or of 1-50 Hz. A low amplitude electrical signalis a signal of 0.5-3.0 T, optionally 1-3 T, optionally 2-3 T, optionally0.5 T, 1 T, 1.5 T, 2 T, 2.5 T, or 3 T and/or of 1-5 0Hz. In certain suchembodiments, the low amplitude signal has a T value lower than the Tvalue of the high amplitude signal.

By way of further example, devices for stimulating nerve activity in thepudendal nerve are described in U.S. Pat. No. 7,571,000 and U.S. Pat.No. 8,396,555, each of which are incorporated herein by reference.

In a third aspect, the invention provides a method of treating bladderdysfunction in a subject by phase-specific stimulation of neuralactivity in a pudendal nerve of the subject, the method comprisingapplying a first signal that stimulates neural activity in the pudendalnerve to produce a first physiological response in the subject, andapplying a second signal that stimulates neural activity in the pudendalnerve to produce a second physiological response in the subject, whereinthe first physiological response and second physiological response aredifferent.

In certain embodiments, the first signal is applied during a fillingphase and the second signal is applied to trigger micturition. Incertain embodiments the first signal is applied during a filling phaseand the second signal is applied during a voiding phase. In certain suchembodiments, the second signal is applied both to trigger micturitionand during the subsequent voiding phase.

In certain embodiments, the first and second physiological responsesproduced in the subject as a result of the first and second signal beingapplied are each selected from one or more of: an increase in bladdercapacity, an increase in bladder voiding efficiency, a decrease inurinary retention, a decrease in the sensation of urgency, a decrease inincontinence and/or a change in external urethral sphincter (EUS)activity towards that of a healthy individual. In certain embodiments,the physiological response produced by the first signal is an increasein bladder capacity and the physiological response produced by thesecond signal is an increase in voiding efficiency.

In certain embodiments, the signals are applied by a neuromodulationapparatus comprising one or more transducers configured to apply thesignals.

In certain preferred embodiments the neuromodulation apparatus is atleast partially implanted in the subject. In certain preferredembodiments, the neuromodulation apparatus is wholly implanted in thesubject. For the avoidance of doubt, the apparatus being “whollyimplanted” does not preclude additional elements, independent of theapparatus but in practice useful for its functioning (for example, aremote wireless charging unit or a remote programmer that is used toprogramme the output of the implanted component or a remote wirelessmanual override unit), being independently formed and external to thesubject's body.

In certain embodiments, the method further comprises detecting one ormore physiological parameters in the subject, said parameters beingselected from: nerve activity in the pudendal nerve, nerve activity inthe hypogastric nerve, nerve activity in the pelvic nerve, muscleactivity in the bladder detrusor muscle, muscle activity in the internalurethral sphincter, muscle activity in the external urethral sphincter,muscle activity in the external anal sphincter, and bladder pressure.

In such embodiments, the first signal is applied when a physiologicalparameter is detected to be meeting or exceeding a first predefinedthreshold value, and the second signal is applied when a physiologicalparameter is detected to be meeting or exceeding a second predefinedthreshold value.

In certain embodiments when the signals are applied by a neuromodulationapparatus, the apparatus further comprises a detector to detect the oneor more physiological parameters in the subject. Such a detector may beconfigured to detect one physiological parameter or a plurality ofphysiological parameters.

It will be appreciated that any two or more of the indicatedphysiological parameters may be detected in parallel or consecutively.

In addition or as an alternative to a detector, the apparatus maycomprise an input element. In such embodiments of the method, thesubject enters data via the input element regarding their behaviourand/or desires to determine when the first and second signals areapplied. For example, the subject may enter via the input element thatthey desire to begin bladder voiding (i.e. intend to begin urinating).In response, the second signal is applied to produce a physiologicalresponse appropriate to the intention to commence bladder voiding—forexample, the signal may increase voiding efficiency. By way of furtherexample, the subject may enter data via the input element indicative ofbehaviour in which bladder filling is appropriate (e.g. sleeping orafter urination, when it is desirous to promote storage). In response tosuch data being entered via the input element, the first signal isapplied to produce a physiological response appropriate for improvedstorage, for example increased bladder capacity.

The input element may communicate directly to the transducer(s), or bein wireless communication as a remote component, for example a componentcarried by the subject. Such arrangements and configurations arediscussed in further detail above.

In certain embodiments, the method is applied unilaterally. That is, insuch embodiments the signals are applied only to the left or only to theright pudendal nerve. In certain alternative embodiments, the method isapplied bilaterally. That is, in such embodiments, a signal is appliedto the left and to the right pudendal nerve. In certain suchembodiments, the first signal may be applied to the right nerve and thesecond signal applied to the left nerve, for example. Alternatively, themethod may be applied bilaterally such that both the first and secondsignals are applied to each of the left and right nerves.

In certain embodiments, the signals stimulate neural activity in thesensory fibres of the nerve to which the signal is applied. In certainsuch embodiments, the signals may selectively stimulate neural activityin the sensory fibres of the nerve to which the signal is applied. Aselective stimulation of neural activity of the sensory fibres of thenerve preferentially increases neural signalling in the sensory fibrescompared to any stimulation of neural activity in the motor nerve fibresof the pudendal nerve. In certain alternative embodiments, the signalincreases signalling activity of the motor fibres of the nerve,optionally selectively increases the signalling activity of the motorfibres of the nerve.

In certain embodiments, the method is a method of treating overactivebladder. In certain embodiments, the method is a method of treatingneurogenic bladder. In certain embodiments, the method is a method oftreating nocturia. In certain embodiments, the method is a method oftreating urinary incontinence. In certain embodiments, the method is amethod of treating urine retention. In certain embodiments, the methodis a method of treating detrusor hyperactivity with impairedcontractility (DHIC). It will be appreciated that the method may treatmore than one of these conditions exhibited by a single subject—by wayof non-limiting example, the method may treat both nocturia and urineretention in the same subject.

In certain embodiments, the treatment of bladder dysfunction isprophylactic treatment. Prophylactic treatment may be such that itprevents an episode of bladder dysfunction. That is, in subjects knownto have bladder dysfunction, the methods of the invention may be used toprevent commencement of an episode of bladder dysfunction, for exampleby using the method to prevent onset of an episode of incontinence.

In certain embodiments, the treatment of bladder dysfunction istherapeutic treatment. That is, the methods of the invention at leastpartially restore the bladder function of the subject. For example,methods according to the invention may result in the subject exhibitinglevels of urinary retention, incontinence, nocturia, urgency and/orfrequency of urination closer to those levels of a healthy subject.

In certain embodiments, treatment of bladder dysfunction is indicated byan improvement in a measurable physiological parameter, for example areduction in number of incontinence episodes, a reduction in the lengthand/or severity of incontinence episode(s), a decrease in urgency ofurination, a decrease in frequency of urination, an increase in bladdercapacity, an increase in bladder voiding efficiency, a decrease inurinary retention, and/or a change in external urethral sphincter (EUS)activity towards that of a healthy individual.

Suitable methods for determining the value for any given parameter wouldbe appreciated by the skilled person.

Each of the first signal and second signal is selected independently ofthe other, so as to achieve the desired physiological response. Theembodiments of the signal may apply to each signal unless specifiedotherwise and are selected independently.

In certain embodiments, each signal is of a modality selected from anelectrical signal, an optical signal, an ultrasonic signal, and athermal signal.

In those embodiments in which the signals are applied by aneuromodulation apparatus, each transducer of the apparatus may becomprised of one or more electrodes, one or more photon sources, one ormore ultrasound transducers, one more sources of heat, or one or moreother types of transducer arranged to put each signal into effect.

In certain embodiments, the first and second signals are each electricalsignals, for example a voltage or current. In such embodiments when thesignal is applied by a neuromodulation apparatus, the one or moretransducers of the apparatus are electrodes. In certain suchembodiments, the one are more transducers are a wire electrode or cuffelectrode, for example a bipolar or tripolar cuff electrode.

In certain embodiments the signals applied comprises a direct current(DC) waveform, or an alternating current (AC) waveform, or both a DC andan AC waveform.

In certain embodiments the signal comprises an AC waveform having afrequency of 0.1-500 Hz, optionally 0.25-100 Hz, optionally 0.5-50 Hz,optionally 1-40 Hz, optionally 1-30 Hz, for example 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28. 29, or 30 Hz, optionally 1, 10, 20 or 30 Hz, optionally 40Hz. In certain embodiments the first signal comprises an AC waveformhaving a frequency of 1-50 Hz, optionally 5-30 Hz, optionally 10-25 Hz,optionally 15-20 Hz, optionally 20 Hz. In certain embodiments the secondsignal comprises an AC waveform having a frequency of 0.5-50 Hz,optionally 0.5-20 Hz, optionally 1-10 Hz, optionally 1 Hz.

In certain embodiments, the signal is a charge-balanced AC waveform. Incertain embodiments, the AC waveform is a biphasic waveform, optionallya charge-balanced biphasic waveform. In certain such embodiments, thewaveform may be symmetrical or asymmetrical. In certain suchembodiments, each phase of the biphasic waveform has a phase durationfrom 0.005 ms to 2 ms, optionally 0.01 to 1 ms, optionally 0.05 to 0.5ms, optionally 0.05 to 0.2 ms, optionally 0.1 ms. In certainembodiments, each phase of a biphasic waveform is of equal duration. Incertain alternative embodiments, each phase is of a different duration.

The AC waveform may be selected from sinusoidal, triangular, square or acomplex waveform.

Typically, effective induction of the intended physiological effectrequires the selection of appropriate stimulation parameters.Stimulation parameters include the stimulation pulseamplitude/intensity, the stimulation pulse duration, and stimulationfrequency.

Relative stimulation pulse intensity can be expressed as multiples (0.1,0.8, 1, 2, 5, etc.) of “T”. “T” is the threshold stimulation intensityrequired to evoke a response. “T” may be the threshold stimulationintensity required to evoke a motor response. In humans, for example,“T” may be defined as the threshold required to evoke a foot or toetwitch, pelvic floor bellowing, pelvic floor contraction (for exampleanal wink), or a reflex electromyogram (EMG) response in the externalurethral sphincter (EUS). Alternatively, “T” may be the thresholdstimulation intensity required to evoke a sensory response, for examplea response perceived by the patient. Preferably, “T” is the thresholdstimulation intensity required to evoke a reflex electromyogram (EMG)response in the external urethral sphincter (EUS).

By way of example, T may be determined as follows: a low frequencyelectrical signal, typically 1 Hz, is applied and the intensity ofstimulation is increased (either by increasing the voltage or thecurrent of the signal, preferably the current) until the pudendal nervestimulation pulse produces a reflex EMG response in the EUS. Thisstimulation intensity is designated T. The absolute thresholdstimulation intensity may vary across individuals, and subsequentexperimental or therapeutic intensities are designated as multiples of Tto provide equivalent relative stimulation intensities.

The desired stimulation intensity (i.e. the desired multiple ofthreshold intensity “T”) can be achieved through controlled variation ofthe current or voltage of the signal, preferably the current.

In certain embodiments the electrical signal has an amplitude value offrom 0.1 T to 15.0 T, where T is a threshold obtained through empiricalmeasurement of the threshold for the stimulation signal to evoke areflex response in the external urethral sphincter or external analsphincter, following application of stimulus to the pudendal nerve. Incertain embodiments, the electrical signal has a T value of 0.1 T-15.0T, 0.5 T-10 T, 0.5 T-2.0 T, 5.0 T-10 T.

In certain embodiments, the first signal is a high amplitude electricalsignal and induces an increase in bladder capacity, and the secondsignal is a low amplitude electrical signal and induces an increase invoiding efficiency. A high amplitude signal is an electrical signal of2.0-10 T, optionally 5-10 T, optionally 8-10 T, optionally 2, 3, 4, 5,6, 7, 8, 9, or 10 T and/or of 1-50 Hz. A low amplitude electrical signalis a signal of 0.5-3.0 T, optionally 1-3 T, optionally 2-3 T, optionally0.5 T, 1 T, 1.5 T, 2 T, 2.5 T, or 3 T and/or of 1-5 0Hz. In certain suchembodiments, the low amplitude signal has a T value lower than the Tvalue of the high amplitude signal.

In certain preferred embodiments, the signal is an electrical signalcomprising an AC waveform of 400 μA 20 Hz, or 50 μA 1 Hz.

In certain embodiments wherein the signal applied is a thermal signal,the signal reduces the temperature of the nerve (i.e. cools the nerve).In certain alternative embodiments, the signal increases the temperatureof the nerve (i.e. heats the nerve). In certain embodiments, the signalboth heats and cools the nerve.

In those embodiments in which the signal applied is a thermal signal andis applied by a neuromodulation device, at least one of the one or moretransducers is configured to apply a thermal signal. In certain suchembodiments, all the transducers are configured to apply a thermalsignal, optionally the same thermal signal.

In certain embodiments, one or more of the one or more transducerscomprise a Peltier element configured to apply a thermal signal,optionally each of the one or more transducers comprises a Peltierelement. In certain embodiments, one or more of the one or moretransducers comprise a laser diode configured to apply a thermal signal,optionally each of the one or more transducers comprises a laser diodeconfigured to apply a thermal signal (e.g. a diode configured to emitinfrared radiation). In certain embodiments, one or more of the one ormore transducers comprise an electrically resistive element configuredto apply a thermal signal, optionally all of the one or more transducerscomprise an electrically resistive element configured to apply a thermalsignal.

In certain embodiments the signal applied is a mechanical signal,optionally an ultrasonic signal. In certain alternative embodiments, themechanical signal applied is a pressure signal.

In certain embodiments the signal applied is an electromagnetic signal,optionally an optical signal. In certain such embodiments when thesignals are applied by a neuromodulation device, the one or moretransducers comprise a laser and/or a light emitting diode configured toapply the optical signal. In some embodiments, the apparatus furthercomprises a fibre optic interface configured to apply said signal fromsaid one or more of the transducers to the nerve.

In certain embodiments, each signal is applied for a set time period,such that a stimulation cycle is defined. In such embodiments, the firstsignal is applied for a first time period and the second signal for asecond time period. In certain such embodiments, the first time periodis of a duration appropriate for a healthy, comfortable storage phase,and the second time period is of a duration appropriate for a healthyvoiding phase.

In certain embodiments when the signals are applied by a neuromodulationapparatus, a third time period follows the second time period duringwhich no signal is applied. An advantage of not applying a signal for aperiod of time following voiding is that battery life of the apparatuscan be prolonged.

In certain embodiments, the first, second (and third when present) timeperiods run consecutively and repeat cyclically.

In certain embodiments, the duration of the each time period isindependently selected. In certain such embodiments, the duration ofeach time period is selected from 5 seconds (5 s) to 24 hours (24 h), 30s to 12 h, 1 min to 12 h, 5 min to 8 h, 5 min to 6 h, 10 min to 6 h, 10min to 4 h, 30 min to 4 h, 1 h to 4 h. In certain embodiments, theduration of each of the first, second, third and fourth time periods is5 s, 10 s, 30 s, 60 s, 2 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h,12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h,24 h. In certain embodiments, the duration of each time period isselected from 0.05 seconds (0.05 s) to 5 second (5 s), optionally 0.1 sto 2 s, optionally 0.1 s to 1 s, optionally 0.2 s to 0.8 s, optionally0.3 s to 0.7 s, optionally 0.4 s to 0.6 s, optionally 0.5 s. Forexample, in certain such embodiments, the signal may be applied for aperiod of 0.1 ms every 0.5 s (that is, with a period of 0.5 s).

In certain embodiments, the controller is configured to cause the signalto be applied for a specific amount of time per day. In certain suchembodiments, each signal may be applied for 10 min, 20 min, 30 min, 40min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22h, 23 h per day. In certain such embodiments, each signal is caused tobe applied continuously for the specified amount of time. In certainalternative such embodiments, each signal may be applied discontinuouslyacross the day, provided the total time of application amounts to thespecified time.

In certain embodiments wherein the signal is applied intermittently,each signal is applied for a specific amount of time per day. In certainsuch embodiments, the signal is applied for 10 min, 20 min, 30 min, 40min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22h, 23 h per day.

In certain embodiments wherein the modulation is bilateral, each signalis applied by a single neuromodulation apparatus. In certain alternativeembodiments, the left-side signal(s) is applied by one neuromodulationapparatus and right-side signal(s) is applied by another neuromodulationapparatus.

In a fourth aspect, the invention provides use of a neuromodulationapparatus for treating bladder dysfunction in a subject byphase-specific stimulation of neural activity in a pudendal nerve of thesubject.

In a fifth aspect the invention provides a neuromodulation system, thesystem comprising a plurality of apparatuses according to the firstaspect. In such a system, each apparatus may be arranged to communicatewith at least one other apparatus, optionally all apparatuses in thesystem. In certain embodiments, the system is arranged such that, inuse, the apparatuses are positioned to bilaterally stimulate thepudendal nerves of a patient.

In such embodiments, the system may further comprise additionalcomponents arranged to communicate with the apparatuses of the system,for example a processor, a data input facility, and/or a data displaymodule. In certain such embodiments, the system further comprises aprocessor. In certain such embodiments, the processor is comprisedwithin a mobile device (for example a smart phone) or computer.

In a sixth aspect, the invention provides a pharmaceutical compositioncomprising a compound for treating bladder dysfunction, for use in amethod of treating bladder dysfunction in a subject, wherein the methodis a method according to the second aspect of the invention or accordingto the third aspect of the invention, the method further comprising thestep of administering an effective amount of the pharmaceuticalcomposition to the subject. It is a preferred embodiment that thepharmaceutical composition is for use in a method of treating bladderdysfunction wherein the method comprises applying a signal to a part orall of a pudendal nerve of said patient to stimulate the neural activityof said nerve in the patient, the signal being applied by aneuromodulation apparatus.

In a seventh aspect, the invention provides a pharmaceutical compositioncomprising a compound for treating bladder dysfunction, for use intreating bladder dysfunction in a subject, the subject having anapparatus according to the first aspect implanted. That is, thepharmaceutical composition is for use in treating a subject that has hadan apparatus as described according to the first aspect implanted. Theskilled person will appreciate that the apparatus has been implanted ina manner suitable for the apparatus to operate as described. Use of sucha pharmaceutical composition in a patient having an apparatus accordingto the first aspect implanted will be particularly effective as itpermits a cumulative or synergistic effect as a result of thecombination of the compound for treating bladder dysfunction andapparatus operating in combination.

In certain embodiments of the sixth or seventh aspect, the compound fortreating bladder dysfunction is selected from an antimuscarinic compoundand a β-adrenergic receptor agonist, optionally a β3-adrenergic receptoragonist. In certain embodiments, the antimuscarinic compound is selectedfrom darifenacin, hyoscyamine, oxybutynin, tolterodine, solifenacin,trospium, or fesoterodine. In certain embodiments, the β-adrenergicreceptor agonist is a β3-adrenergic receptor agonist, for examplemirabegron. In certain embodiments, the pharmaceutical composition isfor use in treating OAB.

In certain embodiments, the pharmaceutical composition may comprise apharmaceutical carrier and, dispersed therein, a therapeuticallyeffective amount of the compounds for treating bladder dysfunction. Thecomposition may be solid or liquid. The pharmaceutical carrier isgenerally chosen based on the type of administration being used and thepharmaceutical carrier may for example be solid or liquid. The compoundsof the invention may be in the same phase or in a different phase thanthe pharmaceutical carrier.

Pharmaceutical compositions may be formulated according to theirparticular use and purpose by mixing, for example, excipient, bindingagent, lubricant, disintegrating agent, coating material, emulsifier,suspending agent, solvent, stabilizer, absorption enhancer and/orointment base. The composition may be suitable for oral, injectable,rectal or topical administration.

For example, the pharmaceutical composition may be administered orally,such as in the form of tablets, coated tablets, hard or soft gelatinecapsules, solutions, emulsions, or suspensions. Administration can alsobe carried out rectally, for example using suppositories, locally orpercutaneously, for example using ointments, creams, gels or solution,or parenterally, for example using injectable solutions.

For the preparation of tablets, coated tablets or hard gelatinecapsules, the compounds for treating bladder dysfunction may be admixedwith pharmaceutically inert, inorganic or organic excipients. Examplesof suitable excipients include lactose, maize starch or derivativesthereof, talc or stearic acid or salts thereof. Suitable excipients foruse with soft gelatine capsules include, for example, vegetable oils,waxes, fats and semi-solid or liquid polyols.

For the preparation of solutions and syrups, excipients include, forexample, water, polyols, saccharose, invert sugar and glucose. Forinjectable solutions, excipients include, for example, water, alcohols,polyols, glycerine and vegetable oil. For suppositories and for localand percutaneous application, excipients include, for example, naturalor hardened oils, waxes, fats and semi-solid or liquid polyols.

The pharmaceutical compositions may also contain preserving agents,solubilizing agents, stabilizing agents, wetting agents, emulsifiers,sweeteners, colorants, odorants, buffers, coating agents and/orantioxidants.

Thus, a pharmaceutical formulation for oral administration may, forexample, be granule, tablet, sugar coated tablet, capsule, pill,suspension or emulsion. For parenteral injection for, for example,intravenous, intramuscular or subcutaneous use, a sterile aqueoussolution may be provided that may contain other substances including,for example, salts and/or glucose to make to solution isotonic. Thecompound may also be administered in the form of a suppository orpessary, or may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder.

In a preferred embodiment of all aspects of the invention, the subjector subject is a mammal, more preferably a human. In certain embodiments,the subject or subject is suffering from bladder dysfunction.

The foregoing detailed description has been provided by way ofexplanation and illustration, and is not intended to limit the scope ofthe appended claims. Many variations in the presently preferredembodiments illustrated herein will be apparent to one of ordinary skillin the art, and remain within the scope of the appended claims and theirequivalents.

EXAMPLES Example 1

In the following examples, an accepted animal model of bladderdysfunction was used: the PGE2 (prostoglandin E2) model, in whichinstallation of PGE2 into rats induces a hyperactive bladder response.In addition, a cat model of bladder dysfunction was used. Cats exhibit aurinary function similar to humans, and thus can represent arepresentative model for human disease.

Methodology

Acute experiments were conducted in urethane (1.2 g/kg, SC) anesthetizedfemale Wistar rats using in vivo cystometry (CMG). A PE-90 catheter wasplaced to measure bladder pressure and for intravesical infusion ofsaline and PGE2 (100 μM). Bipolar electrodes were placed on the externalurethral sphincter (EUS) to measure electromyographic (EMG) activity anda bipolar nerve cuff electrode was placed on the sensory branch of thepudendal nerve for stimulation.

In a subset of trials after PGE2 infusion, electrical stimulation of thesensory branch of the pudendal nerve was delivered at differentamplitudes (0.5-10× EUS reflex threshold, T) and frequencies (1-50 Hz).T may be determined as follows: a low frequency electrical signal,typically 1 Hz, is applied and the intensity of stimulation is increased(either by increasing the voltage or the current of the signal,preferably the current) until the pudendal nerve stimulation pulseproduces a reflex EMG response in the EUS. This stimulation intensity isdesignated T. FIG. 3 shows the reflex response in EUS EMG activity usedto determine T.

Results

As shown in FIG. 4 , a “high amplitude” stimulation of the pudendalnerve (200 μA 20 Hz, FIG. 4A, right trace) resulted in an improvedbladder capacity in PGE2 rats compared to control PGE2 rats (FIG. 4A,left trace). The improved bladder capacity is indicated by a slower rateof increase in bladder pressure, as well as a greater absolute bladderpressure before micturition (micturition being indicated by the sharpspike in bladder pressure). The increase in bladder capacity is furthershown in FIG. 5A, where high amplitude stimulation (right hand bar)resulted in a clear increase in bladder volume compared to unstimulatedPGE2 rats (central bar) and to control rats (left hand bar).

FIG. 4B shows that high amplitude stimulation affects external urethralsphincter (EUS) EMG activity (right trace) compared to PGE2 rats inwhich no high amplitude stimulation is applied (left trace). This effectresulted in a decrease in voiding efficiency, as shown in FIG. 5B.

As both effective bladder capacity and voiding efficiency are importantfor healthy bladder activity, it was investigated whether aphase-specific stimulation protocol could improve both bladder capacityand voiding efficiency in PGE2 rats. In particular, it was investigatedwhether both bladder capacity and voiding efficiency could be improvedusing a high amplitude stimulation during filling phase, and a lowamplitude stimulation during voiding phase.

FIG. 6 shows a comparison of high amplitude stimulation (400 μA 20 Hz)alone (A) and phase-specific stimulation (i.e. high amplitudestimulation (400 μA 20 Hz) during filling phase and low amplitudestimulation (50 μA 1 Hz) during voiding phase; FIG. 6B). For highamplitude stimulation only (FIG. 6A), stimulation was stopped justbefore commencement of the voiding phase. For phase-specificstimulation, instead of stopping stimulation just before voiding phase,the stimulation was switched from high amplitude to low amplitudestimulation. The left hand traces show each parameter over a broadertime period, and therefore lower resolution, whilst the right handtraces show each parameter over a shorter time period, thereforeproviding a higher resolution.

With no stimulation, bladder capacity was 0.49 ml and voiding efficiencywas 56% (data not shown). The high amplitude pudendal nerve stimulationalone (FIG. 6A) increased bladder capacity to 0.63 ml, but had only amarginal effect on voiding efficiency (=62%). Phase-specific switchingof stimulation amplitude from high during the filling phase to lowduring the voiding phase increased both bladder capacity (=0.67 ml) andvoiding efficiency (=82%) (FIG. 6B).

FIG. 7 shows data from a cystometrogram in a cat model in which theeffect of low amplitude stimulation (B and C), and high amplitudestimulation (D) on bladder pressure, bladder capacity and voidingefficiency is compared to an unstimulated control (A). Low amplitudestimulation had little effect on bladder capacity or voiding efficiency(with a possible reduction in voiding efficiency observed in (C)).However, high amplitude stimulation greatly improved bladder capacity(D), in accordance with data obtained from the rat model. High amplitudesignalling did not significantly alter voiding efficiency and, due tothe increased bladder capacity, this could lead to issues with undueurine retention. This further supports the rat data and the need for aphase-specific stimulation approach in order to also improve voidingefficiency.

FIG. 8 shows further data from the cat model in which voiding efficiencyas a result of low amplitude stimulation (D, E, F) is compared withvoiding efficiency in control animals (A, B, C). Animals in theintervention group were stimulated during voiding phase with bursts of40 Hz pulses at amplitude to evoke robust contraction of the externalurethral sphincter (0.25-0.9 mA) for 100 ms, with a period of 0.5 s foreach burst (FIG. 8G). These data clearly show increased voidingefficiency as a result of applying the low amplitude signal. Used incombination with the high amplitude signal to improve bladder capacityduring filling, these data support the use of phase-specific stimulationto treat bladder dysfunction.

FIG. 9 shows the effect of transection of the pudendal motor fibres onlyor transection of both sensory and motor fibres on the changes inbladder contraction amplitude and voiding efficiency induced by lowamplitude stimulation of the deep perineal branch of the pudendal nervethat innervates the external urethral sphincter. FIG. 9A and 9C showthat stimulation with the entire nerve intact or following transectionproximal to stimulation of the motor fibres exhibit improved bladdercontraction and improved voiding efficiency, but that this is lost whenboth sensory and motor fibres are transected. This indicates that theimproved voiding is mediated by physiological activation of pudendalsensory fibres occurring as a result of the motor contractions generatedin the external urethral sphincter by motor fibre stimulation. FIG. 9Bshows that stimulation of intact or transected pudendal nerves does notachieve a statistically significant effect on bladder contraction AUC.

These experiments demonstrate that phase specific stimulation of thepudendal nerve is able to provide improved bladder activity across thewhole bladder activity cycle. In particular, phase-specific pudendalnerve stimulation is able to induce improved bladder capacity andimproved voiding efficiency.

1. A neuromodulation apparatus to carry out phase-specific stimulationof a pudendal nerve or subcomponents of a pudendal nerve in response toone or more control signals.
 2. The neuromodulation apparatus of claim1, wherein the one or more control signals is provided in response tooutput of one or more detector elements.
 3. The neuromodulationapparatus of claim 2, wherein the one or more detector elements isresponsive to a physiological parameter selected from nerve activity inthe pudendal nerve, nerve activity in the hypogastric nerve, nerveactivity in the pelvic nerve, muscle activity in the bladder detrusormuscle, muscle activity in the internal urethral sphincter, muscleactivity in the external urethral sphincter, muscle activity in theexternal anal sphincter, and bladder pressure.
 4. The neuromodulationapparatus of claim 1, wherein the one or more control signals isprovided in response to communications from one or more externalsources.
 5. The neuromodulation apparatus of claim 1, wherein the one ormore control signals is provided by a controller according to analgorithm independently received using a communications element.
 6. Theneuromodulation apparatus of claim 2, wherein the one or more controlsignals is provided by a controller according to an algorithmindependently received using a communications element.
 7. Theneuromodulation apparatus of claim 3, wherein the one or more controlsignals is provided by a controller according to an algorithmindependently received using a communications element.
 8. Theneuromodulation apparatus of claim 1, wherein the neuromodulationapparatus comprises a separate control unit.
 9. The neuromodulationapparatus of claim 8, wherein the separate control unit is implanted inthe subject.
 10. The neuromodulation apparatus of claim 1, furthercomprising an input element, wherein the one or more control signals isprovided by a controller in response to inputs a subject entersregarding behaviour and/or desires.
 11. The neuromodulation apparatus ofclaim 1, wherein the neuromodulation apparatus comprises a sensor.
 12. Amethod of treating bladder dysfunction in a subject by phase-specificstimulation of neural activity in a pudendal nerve in a subject.
 13. Amethod according to claim 12, wherein the treatment is characterised byany one or more of a reduction in number of incontinence episodes, adecrease in urgency of urination, a decrease in frequency of urination,an increase bladder capacity, an increase in bladder voiding efficiency,a decrease in urinary retention, a change in external urethral sphincter(EUS) activity towards that of a healthy individual, and/or a change inthe pattern of action potentials or activity of the pelvic nerve,pudendal nerve or hypogastric nerve towards that of a healthyindividual. [page 8 line 13]
 14. A method according to claim 12, whereinthe treatment is characterized by a reduction in the number ofincontinence episodes.
 15. A method according to claim 12, wherein thetreatment is characterized by a decrease in urgency of urination.
 16. Amethod according to claim 12, wherein the treatment is treatment ischaracterized by a decrease in frequency of urination.
 17. A methodaccording to claim 12, wherein the treatment is characterized by anincrease bladder capacity.
 18. A method according to claim 12, whereinthe bladder dysfunction is stress incontinence.
 19. A method of treatingbladder dysfunction in a patient comprising: i. implanting an apparatusof claim 1; ii. positioning a transducer in signaling contact with apudendal nerve of the patient; iii. activating the apparatus.
 20. Amethod according to claim 19, wherein the treatment is characterised byany one or more of a reduction in number of incontinence episodes, adecrease in urgency of urination, a decrease in frequency of urination,an increase bladder capacity, an increase in bladder voiding efficiency,a decrease in urinary retention, a change in external urethral sphincter(EUS) activity towards that of a healthy individual, and/or a change inthe pattern of action potentials or activity of the pelvic nerve,pudendal nerve or hypogastric nerve towards that of a healthyindividual.